Process for the production of 1-aryl-hydropyrazoles



United States Patent The present invention concerns a process for the production of l-aryl-hydropyrazoles, i.e., l aryl pyrazolines and l-arylapyrazolidines. Such l-aryl-hydropynazoles have hitherto been produced from the corresponding aryl hydrazine-s as starting materials. Unsubstituted diamines can be subjected to ring closure by reaction with sodium hypochlorite; however, only low yields of pyrazoline derivatives (about 3 0%) are obtained in mixture with largely resinified by-products.

It has now been found that, unexpectedly, l-aryl-hydropyrazoles of the formula I Ar wherein Ar represents an aromatic carbocyclic radical with maximally 1'2 ring carbon atoms in the carbocyclic moiety, each of R and R independently represents hydrogen or a lower alkyl radical, and each of R and R represents hydrogen or together they represent the direct linkage,

can be produced by treating an aryl-substituted di-amine of formula R CHCH Rz-CH NHg I Ar wherein, Ar, R and R have the meanings given in Formula 1, with a hypohalogenite as defined below.

Lower when used with an aliphatic radical means with from 1 to 4 carbon atoms.

In the above Formulae 1 and 2 Ar is, cfior example, of the naphthalene or acenaphthene series, preferably, however, of the benzene series; the benzene radical can contain inert substituents. Examples of such substituents are: alkyl, such as methyl, ethyl, propyl, isopropyl, n-, sec-, or ter-t.-:butyl, cycloalkyl such as cyclohexyl, aralkyl such as benzyl, or aryl such as phenyl, as well as substituted phenyl groups; particularly =final products of Formulas II and III below, in which it stands tor 2, are obtained from compounds of Formula 2 in which Ar is a benzene nucleus which beans the substituent:

Furthermore, when Ar in Formulas l and 2 is a benzene nucleus, it can also be substituted by alkoxy, cycloalkoxy, aralkoxy or aryloxy groups, e.g. the methoxy, ethoxy, cyclohexyloxy, lbl'lZYlOXY or phenoxy group, halogens such as fluorine, chlorine or bromine or the nitro group, finally also divalent radicals such as, erg. the fused tetramethylene group.

R and R represent, for example, the methyl, ethyl or a pro-pyl or butyl group; preferably, however, they are hydrogen. More particularly, the invention relates to a process for the production of aryl-substituted pyrazolines and pyrazolidines which consists in (a) Mixing a compound of the formula wherein Ar represents an aromatic carbocyclic divalent radical with maximally 12 ring carbon atoms in the carbocyclic moiety,

each of R and R independently, is hydrogen or lower 'alkyl, and n is .an integer ranging from 1 to 2 and is l [tor Ar with more than 6 ring carbon atoms,

with from n to 0+1 moles, per mole of said compound, of a hypohalogenite selected from the group consisting of an alkali metal hypochlorite, e. g., sodium or potassium hypochlorite, calcium hypochlorite, an alkali metal hypobromite, e.g., sodium or potassium hypobromite, calcium hypobromite, an ester of an alkanol of from 4 to 6 carbon atoms with hypochlorous acid and an ester of an .alkanol of irom 4 to 6 carbon atoms, with hypobromous acid, for instance butyl or amyl hypochlorite or hypobromite, in an inert liquid .ia'queous medium at a temperature not exceeding room temperature;

(b) Permitting the reactants in said medium to react while maintaining the temperature thereof in the range between 10 C. and +120 C. of the reaction wherein Ar, R and R have the meanings given above;

(0) Maintaining the pH of the mixture in steps (a) and (b) at at least 7;

(d) Selectively steering the content of said Compounds II and III in said recreation end-product toward of one of said compounds, as desired, by operating within the following limit conditions:

(a) Adding in step (a) about It moles of said hypohalogenite per mole of said compound of Formula I and keeping the temperature in steps (a) and (b) in the range of 10 C. to 0 C., thereby obtaining essentially only a compound of Formula II, and

Adding more than n and at most n+1 moles of said hypohalogenite per mole of said compound of Formula I in step (a), and maintaining the temperature in step (b) above room temperature and preferably at 100 to 120 C., thereby obtaining essentially only a compound of Formula III; and

(e) Recovering the end-product from the reaction mixture.

The starting materials of Formula 2 used according to the invention are obtained by methods known per se, for example, by adding 1 mole of the nitrile of an mfi-unsaturated fatty acid such as acrylic acid nitrile, to 1 mole of the corresponding aromatic amine and subsequent hydrogenation of the nitrile to form the primary amine, or by condensing 1 mole of a 1,3-dichloroor 1,3-dibromoalkane with 1 mole of the desired aromatic amine and converting the 3-chlorol or 3-bromo-alkylarylamines obtained with ammonia in the corresponding 3-aminoalkyl-aryl compounds, or also by condensing 1 mole of an aromatic halogen compound containing a mobile halogen atom with 1 mole of a 1,3-diamino-alkane.

As stated above, the reaction of compounds of Formula 2 (or I, respectively) to' the l-aryl-hydropyrazoles of Formula 1 (II and/or III) is performed in an inert liquid aqueous medium, particularly water or in an inert organic solvent for the reactants which is preferably miscible with Water, e.g., a lower alkanol such as methanol or ethanol or a lower saturated aliphatic ketone such as acetone. At the beginning of the reaction [step (a)] the temperature is advantageously kept as low as feasible, i.e., at temperatures ranging from well below the freezing point of Water up to room temperature (+25 C.) and preferably at about to 0 C., and it can then be raised to the boiling point of the mixture during the reaction, depending on the nature of the final products desired. The end-products which are substantially insoluble in water are isolated and purified by methods known per se, which comprise separation of the watersoluble, inorganic salts formed, and subsequent distillation or recrystallisation, preferably from ether.

In general, a mixture of l-aryl-pyrazolines and l-arylpyrazolidines is obtained by the process according to the invention. The content of pyrazoline in the final product is dependent upon the amount of the hypohalogenite used and on the reaction temperature applied.

When using an excess of about /2 mole of hypohalogenite or more, up to at most 1 mole excess, over the amount stoichiometrically required for the reaction with one mole of diamine, and at boiling temperature, a mixture containing about 50% or more of l-aryl-pyrazoline is obtained, the balance of the mixture consisting essentially of l-aryl-pyrazolidine.

On using about 2 moles of hypohalogenite per mole of diamine, a product consisting substantially of 1-arylaryl-pyrazolidine is obtained.

When using only one mole of hypahalogenite per mole of diamine and maintaining the reaction mixture at 10 to 0 C., a final product consisting essentially only of laryl-pyrazolidine is obtained.

In contrast to the previously known methods, the process according to the invention gives very high, often even almost quantitative yields (90% by Weight and higher) of l-aryl-hydropyrazoles of Formula 1 and can be steered at will, as described above, toward substantially only the respective aryl-pyrazolidine (Formula II) or aryl-pyrazoline (Formula III), as desired. This is all the more surprising as, in view of the present state of the art, it was to be expected that the arylamino com pound used as starting material would be halogenated or oxidised. A great advantage of the process according to the invention consists in the avoidance of aryl hydrazines as starting materials which always contaminate the industrial end-product and strongly discolour the same, and moreover, afford only yields in the order of to 40% The l-aryl-hydropyrazoles of Formula 1 obtained according to the invention are useful as protective agents against oxidation.

Since the substantially pure aryl-pyrazolidines are liquids, and the pure aryl-pyrazolines produced according to the invention form well defined crystals, their application as anti-oxidants in exact dosification is greatly facilitated in these forms compared with the uncrystallised tacky mixture thereof.

Further details can be seen from the following examples. The temperatures are given therein in degrees centigrade, weights in grams (1;), and volumes in millilitres (ml).

Example 1 325 ml. of aqueous sodium hypochlorite solution (16.4% by volume of chlorine=0.75 mol) are added drop by drop within half an hour to 75 g. (0.5 mol) of N-phenyl-trimethylenediamine in a 750 ml. flask fitted with a thermometer, dropping funnel and stirrer. The addition is made while stirring Well and cooling and in such a manner that the temperature does not rise above 20. Cooling is then interrupted and the reaction mixture is stirred for 2 hours at room temperature. 50 ml. (0.5 mol) of concentrated sodium hydroxide solution are then added to the mixture and the whole is then refluxed for 1 hour. After cooling to 50, the organic phase is separated and the aqueous salt solution is washed with 10 ml. of benzene. The organic phase and the benzene solution are then distilled.

67 g. of the theoretical) of an oil are obtained, B.P. l42. On titrimetric determination, this oil consists of 44% of l-phenyl-pyrazolidine and 50% of l-phenyl-pyrazoline.

When using instead of N-phenyl-trimethylenediamine, an equivalent amount of either N-(1-naphthyl)-, N-(2- naphthyl) N- (5 '-acenaphthenyl N- (4-methoxypheny1)-, N-(4-benzyloxyphenyl)-, N-(4'-phenoxyphenyl)-, N-(4-tert. butylphenyl)-, N-(3'-chlorophenyl)-, N-(4'- bromophenyl N- (4'-nitrophenyl N- (4'-cyclohexylphenyl)-, N-(4'-cyclohexyloxyphenyl)-, N-(3,4-tetramethylenephenyl) trimethylene diamine or 1 phenylamino-3-amino-L or -2-methyl propane is used and otherwise the procedure described in the example is followed, then mixtures of 1-(l'-naphthyl)-, l-(2-naphthyl)-, 1-(5-acenaphthyl)-, 1-(4-methoxyphenyl)-, l-(4'- benzyloxyphenyl)-, 1 (4' phenoxyphenyl)-, 1- (4'-tert. buty1phenyl)-, 1-(3'-chlorophenyl)-, 1-(4-bromophenyl)-,1-(4-nitrophenyl)-, 1-(4'-cyclohexylphenyl)-, 1-(4- cyclohexyloxyphenyl)- or 1-(3,4-tetramethylenephenyl)- pyrazoline and -pyrazolidine or of 1-phenyl-5- or -4- methylpyrazoline and pyrazolidine or obtained in similar yields.

The same result is obtained on using sodium hypobromite instead of sodium hypochlorite with otherwise the same procedure.

Example 2 When in Example 1 instead of 325 ml. of sodium hypochlorite solution, 440 ml. thereof are used with otherwise the same procedure as described, then substantially only l-phenyl-pyrazoline is obtained, which is separated as described in the preceding example and recrystallised from ether.

Example 3 Example 1 is repeated, but instead of 325 ml. of sodium hypochlorite solution, 220 ml. thereof are used and the temperature of the reaction mixture is maintained at 5 for about 5 hours. The resulting mixture is then processed as described in Example 1, and a final product consisting substantially only of liquid l-phenylyrazolidine is obtained.

Example 4 440 ml. of sodium hypochlorite solution are added drop by drop at such a rate, while well stirring and cool- 5 ing for 30 minutes, to 150 g. of N,N'-bis(3-aminopropyl)-benzidine in a flask fitted with stirrer, thermometer and dropping funnel, that the temperature does not rise above The reaction mixture is then stirred for a further hours at 0. 50 ml. of concentrated sodium hydroxide are then added to the mixture and the whole is left to stand for 2 hours at room temperature. The end-product so obtained, 4,4'-[bis-pyrazolidinyl-(1")]- diphenyl of the formula CHPNH NH-CH;

l @Q cHroHz \0H2CH3 is filtered off and recrystallised from ether.

The starting material is prepared by hydrogenation of a solution of 198 g. of bis-(3-cyanoethyl)-benzidine in 1.2 litres of methanol which is saturated with ammonia at 4 atmospheres excess pressure. 40 g. of Raney cobalt is used as catalyst. The mixture is hydrogenated at 70- 80 at 100 atmospheres excess pressure for 8 hours minutes until no more hydrogen is taken up. The absorption of hydrogen amounted to 99.5% of the theoretical. The precipitated N,N-bis-(3-aminopropyl)-benzidine is recrystallised from 1 litre of chlorobenzene.

We claim: 1. A process for the production of aryl-substituted pyrazolines and pyrazolidines, which comprises (a) mixing a compound of the formula 11-]. wherein Ar represents an aromatic carbocyclic divalent radical with maximally 12 ring carbon atoms in the carbocyclic moiety, each of R and R independently, is a member selected from the group consisting of hydrogen and lower alkyl, and n is an integer ranging from 1 to 2, and is 1 for Ar with more than 6 ring carbon atoms, with from n to n+1 moles, per mole of said compound, of a hy-pohalogenite selected from the group consisting of an alkali metal hypochlorite, calcium hypochlorite, an alkali metal hypobromite, calcium hypobromite, an ester of an alkanol of from 4 to 6 carbon atoms with hypochlorous acid and an ester of an alkanol of 4 to 6 carbon atoms with hypobromous acid, in an inert liquid aqueous medium, at a temperature not exceeding room temperature;

(b) permitting the reactants in said medium to react while maintaining the temperature thereof in the range between l0 C. and +l C. of the reaction mixture, thereby obtaining a reaction end product consisting essentially of compounds of the formulae l a I'M err-on U wherein Ar, 11, R and R have the meanings given above;

6 (c) maintaining the pH of the mixture in steps (a) and (b) at at least 7;

(d) recovering the end product from the react-ion mixture.

2. In a process for the production of aryl-substituted pyrazolines and pyrazolidines, the step of mixing a compound of the formula R2 R1 ArNHCH( )HCH2-NH2 wherein Ar represents an aromatic carbocyclic radical which maximally 12 ring carbon atoms, and each of R and R independently of each other is a member selected from the group consisting of hydrogen and lower alkyl with, per mole of said compound, from an excess above one and up to a total of about two moles of a hypohalogenite selected from the group consisting of an alkali metal hypochlorite, calcium hypochlorite, an alkali metal hypobromite, calcium hypobromite, an ester of an alkanol of from 4 to 6 carbon atoms with hypochlorous acid and an ester of an alkanol of 4 to 6 carbon atoms with hypobromous acid in an inert liquid medium and raising the temperature above room temperature, thereby efiecting ring closure between the two nitrogen atoms in the above formula and partial dehydrogenation, and thus obtaining a mixture consisting of from 50% to about of the corresponding l-arylpyrazoline and the balance substantially of l-aryl-pyrazolidine.

3. A process for the production of aryl-substituted pyrazolidines, which comprises (a) mixing to react a compound of the formula wherein Ar represents an aromatic carbocyclic radical with maximally 12 ring carbon atoms, and

each of R and R independently, is a member selected from the group consisting of hydrogen and lower alkyl, with one mole, per mole of said compound, of a hypohalogenite selected from the group consisting of an alkali metal hypochlorite, calcium hypochlorite, an alkali metal hypobromite, calcium hypobromite, an ester of an alkanol of from 4 to 6 carbon atoms with hypochlorous acid and an ester of an alkanol of from 4 to 6 carbon atoms with hypobromous acid at a temperature of about 10 to +25 C. in an inert liquid medium and completing the reaction in a medium having a pH of at least 7, thereby obtaining a reaction product consisting essentially of l-aryl-pyrazolidine of the formula R;CHCH2 R2CIH DIIH wherein Ar, R and R have the meaning given above, and (b) recovering the l-aryl-pyrazolidine of Formula II from said reaction product. 4. A process for the production of aryl-substituted pyrazolines and pyrazolidines, which comprises (a) mixing a compound of the formula 7 8 wherein Ar represents an aromatic carbocyclic dimethylene, and a radical represented by the valent radical with maximally 12 ring carbon atoms formula in the carbocyclic moiety, selected from the group consisting of naphthyl, acenaphthyl, phenyl, and R4 phenyl substituted by R3OHN/ lower alkyl, cyclohexyl, benzyl, phenyl, methoxy,

ethoxy, cyclohexyloxy, benzyloxy, phenoxy, fluorine, chlorine, bromine, nitro, fused tetra- 1 methylene, and a radical represented by the formula each of R and R independently of each other is a member R3-O]1N selected from the group consisting of hydrogen and lower alkyl, and R and R are members selected from the group RPCHAJE consisting of hydrogen and the direct linkage R: if taken together with per mole of said compound, from an excess above one and u to a each of R1 and mdependerifly 1s a member total of about two moles of hypohalo genite le ted from th group conslstlng f hy selected from the group consisting of an alkali and lower alkyl metal hypochlorite, calcium hypochlorite, an R3 R are members Selected f h group alkali metal hypobromite, calcium hypobromite, consisting of hydrogen and the direct llnkage if an ester of an alkanol of from 4 to 6 carbon iakenfogether l atoms with hypochlorous acid and an ester of n 13 an.mteger Iangmg f.rom 1 to and 1s 1 for an alkanol of 4 to 6 carbon atoms with hypo- Ar with more than 6 rmg carbon bromous acid in an inert liquid medium and Wlth from n to l Per mole of Sald raising the temperature above room temperapound of a hypohalogemte selected from the group ture thereby effecting ring closure between the consisting of an alkali metal hypochlorite, calcium twonitmgen atoms in the above formula and hypochlorite, an alkali metal hypobromite, calcium Partial dehydrogenation, and thus obtaining a hypobromite, an ester of an alkanol of from 4 to 6 carbon atoms with hypochlorous acid and an ester of an alkanol of 4 to 6 carbon atoms with hypomixture consisting of from 50% to about 100% of the corresponding l-aryl-pyrazoline and the balance substantially of l-aryl-pyraoline.

bromous acid, in an inert liquid aqueous medium, at a temperature not exceeding room temperature; 3 (b) permitting the reactants in said medium to react 6. A process for the production of aryl-substituted pyrazolidines, which comprises (a) mixing to react an compound of the formula while maintaining the temperature thereof in the range between -10 C. and +120 C. of the reaction mixture, thereby obtaining a reaction end product consisting essentially of compounds of the for- 40 mulae wherein Ar represents an aromatic carbocyclic radill I B2 I f:al wit}? maximally 12 ringf carbltlnrllJ altoms, selecteii rom t e group consisting o nap t y acenaphthy g /CHCH phenyl and phenyl substituted by l /N- lower alkyl, cyclohexyl, benzyl, phenyl, methoxy, CHTNH ethoxy, cyclohexyloxy, benzyloxy, phenoxy, i (H) fluorine, chlorine, bromine, nitro, fused tetramethylene and a radical represented by the R; R, R1 R1 formula H t tH l at OH=N J N=CH 3 N n--! (111) R1 CH CH/ wherein Ar, 11, R and R have the meanings given above; (0) maintaining the pH of the mixture in steps h of (a) and (b) at at least 7; R and R independently, is a member selected recovering the end Product from the reaction 50 from the group consisting of hydrogen and lowmixture. er alkyl and 5. In a process for the production of aryl-substituted R and R are members selected from the PYmZOhIleS and Pyrazolidihes, the p of mixing a group consisting of hydrogen and the direct compound of the formula linkage if taken together with one mole, per R2 R1 55 mole of said compound, of a hypohalogenite I selected from the group consisting of an alkali A1'Nl1CHGHCHz-NH2 metal hypochlorite, calcium hypochlorite, an alkali metal hypobromite, calcium hypobromite, wherein Ar represents an aromatic carbocycllc radlcal an ester f an lk l f 4 to 6 carbon atoms with maximally 12 ring carbon atoms, selected from with hypochlorous acid and an ester f an the group Consisting p y acenaphthyl, alkanol of from 4 to 6 carbon atoms with p y and p y shhstltuted y hypobromous acid at a temperature of about lower y cyclohexyl, benzyl, p y y, -10 to +25 c. in an inert liquid medium Y, Y Y Y, Y Y, p y, and completing the reaction in a medium havfluorine, chlorine, bromine, nitro, fused tetraing a pH of at least 7, thereby obtaining a re 9 10 action product consisting essentially of l-aryl- References Cited by the Examiner Pyrazohdme of the formula Luttringhaus et a1., Naturwissenschaften, vol. 44, page R OH-CH1 442 (1957).

A Luttringhaus et al., Chemische Berichte, v01. 92, pages in (11) JOHN D. RANDOLPH, Acting Primary Examiner. wherein Ar, R and R having the meaning given above O AS RIZZO, NATALIE TROUSQF,

and Assistant Examiners.

(b) recovering the l-aryl-pyrazolidine of Formula II 10 from said reaction product. 

2. IN A PROCESS FOR THE PRODUCTION OF ARYL-SUBSTITUTED PYRAZOLINES AND PYRAZOLIDINES, THE STEP OF MIXING A COMPOUND OF THE FORMULA
 3. A PROCESS FOR THE PRODUCTION OF ARYL-SUBSTITUTED PYRAZOLIDINES, WHICH COMPRISES (A) MIXING TO REACT A COMPOUND OF THE FORMULA 